This background information is provided for the purpose of making information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should it be construed, that any of the preceding information constitutes prior art against the present invention.
HIV causes a global pandemic with >36 million people infected worldwide. HIV infection in the body exists in both an actively replicating state (causing disease symptoms etc.) and a dormant, non-replicating state (which lays in wait). While current anti-retroviral therapy (ART) can efficiently reduce HIV viremia to undetectable levels in infected individuals, it cannot eliminate residual HIV due to establishment of latency. In particular, because latent HIV is not replicating, the anti-retroviral therapy does not eradiate (i.e., cure or eliminate) latent HIV and the patient remains infected with the virus.
While HIV-infected individuals can generally live normal lives under ART, the effects of HIV infection remain significant in viral-suppressed individuals, continuously causing a range of metabolic, immunologic, and neurologic co-morbidities. ART can only affect cells harboring actively replicating virus but not latent reservoirs, which poses a major obstacle to eradicate HIV with current ART-based treatment paradigm. In particular, low levels of HIV replication continuously occur in ART-suppressed individuals and the latent reservoir is capable of rapidly producing infectious virus when ART is discontinued. Therefore, ART treatment requires life-long administration in order to achieve sustained viral suppressed.
Also critically, ART does not fully prevent pathology or restore a normal lifespan in HIV-infected patients. With expanded usage of ART, HIV is becoming more drug resistant, which also markedly erodes the efficacy of ART. Due to these significant limitations, new treatment paradigm that targets latent HIV reservoirs for eradication is needed and has been recognized as a high research priority.
Development of novel strategies targeting latent HIV reservoir has therefore been a high research priority for HIV cure. To date, several categories of LRAs, based on various mechanisms, have been identified and tested in HIV latency cellular models and/or clinical studies, including the histone deacetylase inhibitors (HDACis), bromodomain inhibitors (BETis), PKC agonists, TLR agonists and cytokines.
Current efforts targeting latent HIV for eradication or cure mainly focus on four categories: reactivating latent HIV to ‘purge’ the virus out of reservoirs (shock), killing of reactivated HIV by strengthening the immune response (kill), keeping the latent reservoirs permanently silenced or targeting latent HIV in CD4+ T cells via novel gene therapy approaches. As the first step of the “shock and kill” approach, discovery and development of effective latency-reversing agents (LRAs) to reactivate latent HIV from reservoirs are critical.
Nevertheless, existing LRAs manifest various significant limitations. To date, a number of latency reversing agents (LRAs), including small pharmacological compounds, have been tested for activating latent HIV in a so-called ‘shock and kill’ HIV eradication strategy. Existing LRAs, however, demonstrate various significant limitations, such as inefficiency to activate latent HIV in primary cells, limited efficacy in vivo and undesirable toxicity profiles.
Therefore, discovery and development of novel mechanism-based LRAs, especially those also able to activate HIV in primary cells, represent a major knowledge gap and are urgently needed to further expand and complement existing LRAs pool for improving the “HIV Shock and Kill” strategy.
To that end, there is a great need for the discovery and development of novel LRAs, based on new mechanisms of action, to complement existing LRAs for more efficiently activating latent HIV as part of the “shock and kill” approach.
The inventors have surprisingly discovered certain novel EPAC1 activators, including compound ZL0568 (FIG. 2B), that target EPAC for more efficiently activating latent HIV.